Abstract
Abstract
Rationale
Pulmonary veno-occlusive disease (PVOD) is a progressive and lethal disease cured only lung transplant. While genetic mutations in
EIF2AK4
have been identified in some cases, 70% of PVOD patients have no known etiology.
Objectives
To construct a single-cell atlas to define the cellular and molecular constituents driving pathophysiology in PVOD.
Methods
Lung samples were collected from four idiopathic non-
EIF2AK4
mutation pediatric and adult PVOD patients and age-matched controls. Analyses of single-cell RNA sequencing, Xenium spatial transcriptomics, and immunohistochemistry were performed to identify cell state changes and differential gene expression between controls and PVOD and subsequent transcriptome comparison between our PVOD and published pulmonary arterial hypertension (PAH) datasets.
Measurement and Main Results
The single-cell atlas reveals marked changes in the PVOD endothelium compared to controls. EndMT and ectopic COL15A1+ systemic venous shunts and pulmonary vein endothelium are hallmarks of PVOD. Molecular analyses reveal activation of the integrated stress response (ISR)/ATF4, TGFβ signaling, MAPK signaling, and BRD4 are potential key players in the pathophysiology of PVOD. While PVOD and PAH share both pathological and some molecular mechanisms, ISR and TGFβ signaling are more prominent in PVOD than PAH.
Conclusions
These data indicate that endothelial dysfunction is a primary etiology in the development of PVOD with activation of multiple pathways with druggable targets.
At a Glance Commentary
Scientific Knowledge of the Subject
Pulmonary veno-occlusive disease (PVOD) is driven by progressive vasculopathy of the pulmonary veins and capillaries that results in significant pre-lung transplant mortality. Only 30% of PVOD cases can be explained by genetic mutations in
EIF2AK4
, a critical protein translation factor associated with the integrated stress response. Thus, the majority of PVOD cases have no known molecular and cellular etiologies.
What This Study Adds to the Field
This study generated a cell atlas of idiopathic PVOD in patients with the more common, non-
EIF2AK4
mutation etiology. This cell atlas defines pathological cell state changes in the lung vasculature including aberrant populations in the endothelium of veins and capillaries. These data also provide key insight into the molecular underpinnings driving PVOD disease and identified both novel and common targetable pulmonary vascular disease pathways with known drugs that are currently under investigation or FDA approved.